Ovarian cancer is the most lethal of all the gynecologic cancers. Due to non-specific symptoms the disease frequently remains undetected until well advanced. Despite improved and ever more aggressive therapy approaches, 5-year survival is less than 50%. Early detection of ovarian cancer is critical to improve survival, but currently less than 30% of cases are diagnosed when early stage disease is still confined to the ovary. Ovarian cancer outcomes could be improved by the development of a non-invasive molecular imaging strategy that can reliably distinguish malignant from benign ovarian masses and detect early stage asymptomatic disease. Ultrasound (US) is the current first line ovarian imaging test in most clinical situations, but has important limitations leading to suboptimal performance in the screening setting. A strategy to improve sensitivity and specificity of US may help change the modality into a useful tool for early detection of ovarian cancer. Pre-clinical studies demonstrate that ultrasound performance can be improved by the addition of molecularly targeted microbubble contrast agents that provide molecular information on the ovarian cancer associated neo-vasculature. Molecularly targeted CEUS may be applied to ovarian cancer early detection as well as selecting patients for and monitoring the response of ovarian cancer to anti-angiogenic therapy. Our long-term translational goal is to apply the molecularly targeted CEUS approach in a multi- modal ovarian cancer screening strategy, especially in defined high-risk patient populations. As an important step towards our long-term goal we are proposing to conduct a Phase I/II clinical trial of VEGFR2-targeted CEUS for ovarian cancer-associated neo-angiogenesis imaging in patients with suspected ovarian cancer and in patients at high risk for ovarian cancer to assess the detection limits and background signal. We will elucidate the influence of physiologic wound- healing associated physiologic angiogenesis on imaging findings and the optimal imaging time point within the menstrual cycle in premenopausal patients. We are also proposing to use excess tissue material from clinically indicated histopathology work-up for exploratory studies to further validate novel endothelial cell surface proteins that may be optimal future targets for the imaging of ovarian cancer-associated neo-angiogenesis. These novel markers could serve as complementary targets for future multivalent microbubbles that have the potential to further increase the sensitivity and specificity of the method by addressing multiple targets simultaneously.